Xiaoguang Sun

Lactate dehydrogenase a in cancer: A promising target for diagnosis and therapy

One of the principal biochemical characteristics of malignant cells compared to normal cells is a metabolic switch from oxidative phosphorylation to increased glycolysis, even under hypoxic conditions, and is termed the Warburg effect. Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate and is considered to be a key checkpoint of anaerobic glycolysis. It is elevated in many types of cancers and has been linked to tumor growth, maintenance, and invasion; therefore, its inhibition may restrict the energy supply in tumors and thereby reduce the metastatic and invasive potential of cancer cells. This enzyme is receiving a great deal of attention as a potential diagnostic marker or a predictive biomarker for many types of cancer and as a therapeutic target for new anticancer treatments. In this review, we summarize the role of LDHA in cancer, discuss its potential significance in clinical diagnosis and prognosis of cancer, and propose LDHA as a novel target for the inhibition of tumor growth and invasiveness.

18F-FDG-PET evaluation of treatment response to neo-adjuvant therapy in patients with locally advanced rectal cancer: a meta-analysis.

The purpose of this meta‐analysis was to evaluate the utility of positron emission tomography (PET) using fluor‐18‐deoxyglucose (FDG) to predict the response of rectal cancer to neo‐adjuvant therapy. All previously published studies on the role of FDG‐PET in predicting the response of rectal cancer to neo‐adjuvant therapy were collected. Pooled sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated using statistical software. A total of 28 studies, comprising 1,204 patients with rectal cancer, were included in the meta‐analysis. Pooled sensitivity, specificity, PPV and NPV for FDG‐PET predicting the response to therapy was 78% [95% confidence interval (CI): 75–82%], 66% (95% CI: 62–69%), 70% (95% CI; 66–73%) and 75% (95% CI: 71–0.79%), respectively. The included studies were of a relatively high methodological quality according to the QUADAS (quality assessment of studies of diagnostic accuracy included in systematic reviews) criteria. Based on the subgroup analyses, there was no significant difference between the response index, the standardized uptake value and the visual response score in predicting the therapy response. However, the accuracy of the group that underwent PET scanning during therapy showed significantly higher values (sensitivity 86% and specificity 80%) than the group that was scanned after completion of the therapy. Therefore, FDG‐PET is valuable for predicting the response of rectal carcinoma to neo‐adjuvant therapy, and early evaluation of response during the therapy may be more promising. However, additional studies using prospective clinical trials will be required to assess the clinical benefit of this strategy.

Proviral Insertion in Murine Lymphomas 2 (PIM2) Oncogene Phosphorylates Pyruvate Kinase M2 (PKM2) and Promotes Glycolysis in Cancer Cells

Background: The protein-serine/threonine kinase PIM2 regulates glycolysis, but the mechanism is not fully elucidated. Results: PIM2 interacts with PKM2 and phosphorylates PKM2 on the Thr-454 residue. Conclusion: This phosphorylation of PKM2 increases glycolysis and proliferation in cancer cells. Significance: PIM2-dependent phosphorylation of PKM2 is critical for regulating the Warburg effect in cancer, highlighting PIM2 as a potential therapeutic target. Pyruvate kinase M2 (PKM2) is a key player in the Warburg effect of cancer cells. However, the mechanisms of regulating PKM2 are not fully elucidated. Here, we identified the protein-serine/threonine kinase PIM2, a known oncogene, as a novel binding partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis, co-activating HIF-1α and β-catenin, and cell proliferation, while enhancing mitochondrial respiration of cancer cells. These findings demonstrate that PIM2-dependent phosphorylation of PKM2 is critical for regulating the Warburg effect in cancer, highlighting PIM2 as a potential therapeutic target.

Diagnostic value of FDG-PET in recurrent colorectal carcinoma: A meta-analysis

Accurate detection of recurrent colorectal carcinoma remains a diagnostic challenge. The purposes of this study were to evaluate the diagnostic value of Positron emission tomography (PET) using fluor‐18‐deoxyglucose (FDG) in recurrent colorectal carcinoma with a meta‐analysis. All the published studies in English relating the diagnostic value of FDG‐PET in the detection of recurrent colorectal carcinoma were collected. Methodological quality of the included studies was evaluated. Pooled sensitivity, specificity and diagnostic odds ratio and SROC (summary receiver operating characteristic curves) were obtained by the statistical software. Twenty‐seven studies were included in the meta‐analysis. The pooled sensitivity and specificity for FDG‐PET detecting distant metastasis or whole body involvement in recurrent colorectal carcinoma were 0.91 (95% CI 0.88–0.92) and 0.83 (95% CI 0.79–0.87), respectively. The pooled sensitivity and specificity for FDG‐PET detecting hepatic metastasis were 0.97 (95% CI 0.95–0.98) and 0.98 (95% CI 0.97–0.99). The pooled sensitivity and specificity for pelvic metastasis or local regional recurrence were 0.94 (95% CI 0.91–0.97) and 0.94 (95% CI 0.92–0.96). FDG‐PET is valuable for the assessment of recurrent colorectal carcinoma.

Inhibition of Lipolysis by Mercaptoacetate and Etomoxir Specifically Sensitize Drug-Resistant Lung Adenocarcinoma Cell to Paclitaxel

Chemoresistance is a major cause of treatment failure in patients with lung cancer. Although the extensive efforts have been made in overcoming chemoresistance, the underlying mechanisms are still elusive. Cancer cells reprogram cellular metabolism to satisfy the demands of malignant phenotype. To reveal roles of cancer metabolism in regulating chemoresistance, we profiled the metabolic characteristics in paclitaxel-resistant lung cancer cells by flux assay. Glucose and oleate metabolism were significantly different between resistant and non-resistant cells. In addition, targeting metabolism as a strategy to overcome drug resistance was investigated using specific metabolic inhibitors. Inhibition of glycolysis and oxidative phosphorylation by 2-deoxyglucose and malonate, respectively, potentiated the effects of paclitaxel on nonresistant lung adenocarcinoma cells but not paclitaxel-resistant cells. By contrast, inhibition of lipolysis by mercaptoacetate or etomoxir synergistically inhibited drug-resistant lung adenocarcinoma cell proliferation. We conclude that lipolysis inhibition potentially be a therapeutic strategy to overcome drug resistance in lung cancer.

18F-FDG-PET evaluation of pathological tumour response to neoadjuvant therapy in patients with NSCLC.

ObjectivesThe ability to identify potential responders to neoadjuvant treatment may improve patient selection or surgery and may help in the development of response criteria suitable for routine monitoring of response. The aim of this study was to evaluate the value of PET in predicting the pathological tumour response of non-small-cell lung cancer (NSCLC) to neoadjuvant therapy using a meta-analysis. MethodsAll available published studies investigating the value of PET in predicting the pathological response of NSCLC to neoadjuvant therapy were collected. Pooled sensitivity and specificity data were obtained using statistical software. Subgroup analysis was performed to explore the sources of heterogeneity. ResultsA total of 13 studies comprising 414 patients with NSCLC were included in the meta-analysis. Pooled sensitivity, specificity, positive predictive value and negative predictive value for PET-predicted response was 83% [95% confidence interval (CI); 76–89%], 84% (95% CI; 79–88%), 74% (95% CI; 67–81%) and 91% (95% CI; 87–94%), respectively. Significant heterogeneity (P<0.05) was observed. On the basis of our subgroup analyses, methodological quality could be responsible for this heterogeneity in our metaregression. The predictive value of PET in NSCLC patients with pathological response (considered the gold standard) was significantly higher than that of computed tomography (P<0.05). ConclusionPET scanning has an important role in predicting nonresponders to neoadjuvant therapy in cases of NSCLC, and the predictive value of PET for evaluating pathologically documented responses is superior to that of computed tomography. However, additional evaluations using prospective clinical trials will be required to assess the clinical benefit of this strategy.

Changes in 18F-FDG Uptake Within Minutes After Chemotherapy in a Rabbit VX2 Tumor Model

The purpose of this study was to investigate whether 18F-FDG PET/CT can be used for in vivo chemosensitivity testing and to determine the optimal time point for observation. Methods: Forty-two rabbits with 84 implanted VX2 squamous cell tumors were randomized into a control group (n = 10) and a treatment group (n = 32). 18F-FDG PET/CT was performed the day before intravenous administration of cisplatin (4 mg/kg) and at 95–100 min (day 0), day 1, day 7, and day 14 afterward. In the control group, 18F-FDG PET/CT images were acquired at the same time points but without cisplatin administration. Maximum standardized uptake value (SUV) and mean SUV were analyzed. On the basis of tumor volume, we categorized animal tumors into a sensitive group and an insensitive group. If tumor volume doubled by day 7, the tumor was considered insensitive. Results: On day 0, maximum SUV and mean SUV were significantly different between the sensitive group and the insensitive and control groups (P < 0.05 for both). In the sensitive group, the average change from the pretherapy values was −48.96% ± 12.27% for maximum SUV and −51.63% ± 10.45% for mean SUV. SUV did not significantly differ between the groups at any other points (days 1–14). On day 0, tumor volume was not significantly different between the control group and the sensitive or insensitive groups. After cisplatin administration, the size of the VX2 xenograft tumors increased slowly. Tumor necrosis fractions on days 7 and 14 were significantly greater in the sensitive group than in the insensitive or control group. Viable tumor cells on days 7 and 14 were less numerous in the sensitive group than in the insensitive or control group. A significant difference in inflammatory cells was seen between the sensitive and insensitive groups on days 7 and 14 (P < 0.05 for both). No significant differences in inflammatory cells or viable tumor cells were seen between the insensitive and control groups at any time points from before therapy to day 14 (P > 0.05 for all). A slight increase in viable tumor cells and inflammatory cells was seen in the sensitive group on day 14, compared with day 7. Conclusion: When 18F-FDG was injected as early as 40 min after administration of chemotherapy, PET showed significantly decreased in vivo uptake of the tracer in chemoresponsive tumors. This finding suggests that 18F-FDG PET may be able to discriminate sensitive from insensitive tumors if the imaging is performed immediately after a test dose of chemotherapy. The optimal observation time and methodology for various chemotherapy–tumor combinations will need to be studied to confirm whether this approach can be generalized.

Inhibition of SREBP increases gefitinib sensitivity in non-small cell lung cancer cells

The clinical success of EGFR inhibitors in patients with lung cancer is limited by the inevitable development of treatment resistance. Here, we show that inhibition of SREBP increase gefitinib sensitivity in vitro and in vivo. Interference of SREBP1 binding partner MARVELD1 potentiate the therapeutic effect of gefitinib as well. Mechanistically, SREBP inhibition decreases the cell membrane fluidity, results in a decreased tyrosine phosphorylation of EGFR. Therefore, targeting lipid metabolism combined with EGFR-TKIs is potentially a novel therapeutic strategies for cancer treatment.

Lens culinaris agglutinin-reactive α-fetoprotein decline after transcatheter arterial chemoembolization in patients with hepatocellular carcinoma predicts survival

BACKGROUND Lens culinaris agglutinin-reactive α-fetoprotein (AFP-L3) is a fucosylated fraction of AFP that is highly specific for hepatocellular carcinoma (HCC). We studied the relationship between AFP-L3 response and treatment outcome in terms of radiologic response and overall survival in patients undergoing transcatheter arterial chemoembolization (TACE). METHODS We retrospectively analyzed 152 patients with advanced HCC undergoing TACE. Serum AFP-L3 and AFP levels were measured simultaneously with a novel lectin dual-label time-resolved immunofluorometric assay (lectin dual-label TRFIA). AFP-L3 response was defined as a ≥20% reduction in AFP-L3 level after a minimum of 2 cycles of chemotherapy. RESULTS A total of 47 AFP-L3 responders had improved median overall survival of 42.9 months compared with 15.4 months in nonresponders (P<0.0001), and AFP-L3 response was strongly associated with radiologic response (P<0.0001). The combination of AFP-L3 response and serum AFP response provided further prognostic information. On multivariate analysis, the prognostic value of AFP-L3 response was independent of maximum tumor diameter and BCLC stage. CONCLUSION A significant reduction in AFP-L3 in patients with advanced HCC is an important predictor of survival. Achieving an AFP-L3 response should be one of the therapeutic intents of TACE.

Lactate promotes resistance to glucose starvation via upregulation of Bcl-2 mediated by mTOR activation

Solid tumors grow faster and need more glucose than normal tissue; however, due to poor angiogenesis and excessive growth, tumors remote from blood vessels are always under glucose starvation. Even so, cancer cells remain alive in vivo. Thus, making cancer cells sensitive to glucose depletion may potentially provide an effective strategy for cancer intervention. Tumors that obtain sufficient glucose generate a large amount of lactate. Therefore, we proposed that lactate, a tumor microenvironment factor, may allow cancer cells to develop resistance to glucose starvation-induced death. We cultured cancer cells in no-glucose medium and added lactate to the medium. During the experiment, lactate helped cancer cells to escape from glucose starvation-induced cell death, without using lactate as an energy substrate, resulting in activation of Akt through PI3K. Akt activation plays a central role in cell growth through the activation of mammalian target of rapamycin (mTOR). Alteration of the PI3K/Akt/mTOR signaling pathway by inhibiting apoptosis induced specific upregulation of B-cell lymphoma 2 (Bcl-2) through translational control. In conclusion, this study showed that lactate rescues cancer cells from glucose starvation-induced cell death through regulation of the PI3K/Akt/mTOR/Bcl-2 signaling pathway. These data suggest that lactate is an important determinant of the sensitivity of tumors to glucose starvation, and reducing lactate or inhibiting the PI3K/Akt/mTOR/Bcl-2 signaling pathway may influence the response of cancers to glucose starvation.